a. Field of the Invention
The present invention relates generally to the methods for the treatment of neurologic dysfunction, and, more particularly, to methods for treatment of the symptoms of depression, autism spectrum disorder (ASD) and schizophrenic by administration of compositions that serve to increase the activity of Monoamine Oxidase-A (MAO-A).
b. Related Art
It is increasingly recognized that many disorders previously thought to be psychological in nature are, in actuality, to a greater or lesser extent the result of neurologic dysfunction. With respect to the present invention, examples of conditions stemming from what are believed to be neurologic dysfunctions include but are not limited to major depression, autism spectrum disorder (ASD) and schizophrenia.
Major depression is a serious affective disorder (mood disorder). Common symptoms include: persistent sadness; feelings of hopelessness or pessimism; feelings of guilt, worthlessness, helplessness; loss of interest in hobbies and activities that once gave pleasure; decreased energy; memory deficits and difficulty in making decisions and concentrating; insomnia, early morning wakening, or oversleeping; appetite loss and/or weight loss or overeating and weight gain; suicide ideations or attempts, thoughts of death; physical ailments such as headaches, chronic pain or digestive problems that do not respond to treatment. These symptoms can range from mild to severe, but persist for two weeks or more and often interfere with a person's daily functioning.
According to the National Institute of Mental Health, about 18 million Americans are afflicted with major depression annually. It has been estimated to be the second leading cause of disability, surpassed only by heart disease. Depression is about twice as prevalent in women than men and its occurrence is about two to three times more common in first degree relatives of depressed persons.
The causes of depression have not been conclusively identified, but it has heretofore generally been believed that depression is a result of inadequate levels of the neurotransmitters, serotonin and norepinephrine, with most emphasis on the former. Prior efforts at treatment of depression have thus concentrated on increasing the levels of serotonin and/or norepinephrine: Past and current antidepressant treatments have consisted of primarily monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. All of these treatments have been believed to function by increasing the amount of serotonin in nerve synapses (e.g., Sigma-Aldrich, 2003).
The first antidepressant therapies were monoamine oxidase inhibitors (MAO inhibitors) such as iproniazid. Monoamine oxidase has two subtypes, A and B. Monoamine oxidase A (MAO-A) metabolizes both norepinephrine and serotonin. Thus, it has been believed that the antidepressant effect of MAO inhibitors is the result of increased levels of serotonin and norepinephrine due to the MAO inhibitors blocking the breakdown of these neurotransmitters. Despite the proven efficacy of the MAO inhibitors as antidepressants, their use today has become very limited due to the serious side effects associated with MAO inhibitors. One of the side effects is hepatoxicity: MAO is a very important amine-oxidizing enzyme in the liver and the brain, and the inactivation of MAO interferes in the breakdown of tyramine (tyramine is a common amine in food and some beverages). MAO inhibitors can consequently cause excessive amounts of tyramine to accumulate in the brain, which can result in a hypertensive crisis or death. Most of the older MAO inhibitors were irreversible non-selective inhibitors meaning that they inhibited both MAO-A and MAO-B and predominantly inhibited the MAO-B. Today there are several reversible selectively specific MAO-A inhibitors being studied or in use outside of the United States: Because of their reversibility they have a short duration of action, and thus are somewhat less apt to result in the inactivation of liver metabolism and the accumulation of tyramine.
Another class of antidepressant is tricyclic antidepressants, such as imipramine. Tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin by blocking the reuptake transporters, resulting in increased levels of these neurotransmitters in the nerve synapses (synaptic clefts). Because of the increased levels of the norepinephrine in the nerve synapses excessive cardiac stimulation can result. These cardiac arrhythmias can be difficult to treat and be potentially life threatening. These side effects prompted the development of selective serotonin reuptake inhibitors (SSRIs), which are the most commonly used antidepressants today. Although the SSRIs do not result in increased concentrations of norepinephrine and therefore avoid causing cardiac arrhythmias, the elevation in the serotonin in the nerve synapses can cause agitation, restlessness, gastrointestinal distress and sexual side effects all of which are common symptoms of depression (Sigma-Aldrich, 2003).
The clinical success of SSRIs in treating depression has been interpreted as supporting the prevalent hypothesis that the etiology of depression is a serotonin deficiency. However, it is not clear as to how the SSRIs, tricyclic antidepressants, or MAO inhibitors relieve depression since there is a lag of several weeks before any mood-elevating effects are noticed after these treatments are started, despite the rapid increase in the levels of serotonin in the nerve synapses. Furthermore, the elevated concentrations of the serotonin in the nerve synapses have been shown to cause symptoms common in depression (Sigma-Aldrich, 2003). Also, the administration of serotonin or its precursors was markedly less effective or not effective at all when compared to the MAO inhibitors, tricyclic antidepressants, or the SSRIs in depressed persons (Beckmann and Kasper (1983), Fortschr. Neurol. Psychiatr. 511(5): 176-82; Nolen et al, (1985), Br. J. Psychiatry 147.16-22). So the question arises, if depression is due to the deficiency of serotonin, then why isn't the administration of serotonin or its precursors L-tryptophan or 5-Hydroxytryptophan more or at least equally effective as these antidepressant treatments? And if depression is due to the deficiency of serotonin, then why does it take several weeks before any benefit may be seen from these antidepressant therapies, even though increase the concentration of serotonin in the nerve synapses almost immediately upon administration? As will be described below, the present invention is founded on a new hypothesis that offers a possible resolution to these issues.
Autism Spectrum Disorder, also known as Pervasive Developmental Disorders (PDD) encompasses at least five disorders: Autism; Asperger Syndrome; Rett Syndrome; Childhood Disintegrative Disorder; and Pervasive Developmental Disorder Not Otherwise
Specified (atypical autism). Childhood autism, also known as autistic disorder or infantile autism is a neuro-developmental condition that is characterized by impairment in social interaction, impairment in communication and restricted or stereotyped patterns of behavior and interest usually manifested before the age of 3 years. Core symptoms of ASD are the following: impaired communications (verbal and/or nonverbal); repetitive movements. Other common symptoms of ASD include: impaired social skills; delayed or unusual speech patterns; hyper or hypo sensitivity to light, sound, crowd and other external stimulation; some degree of fine and gross motor difficulty; repetitive behaviors and ritualized activities; aloofness or disengagement with surrounding environment, inability to handle stress or change in routine or environment; some patients have a degree of mental retardation and one in four develop seizures. The severity of these symptoms is very individualized in persons diagnosed with ASD.
The incidence of ASD has increased dramatically over the last decade and today 1 in 150 children are diagnosed as having ASD (http://www.cdc.gov/ncbddd/autism/faq_prevalence.htm). The cause of ASD still eludes the medical community, but several factors have been implicated such as hereditary, heavy metal toxicity, vaccinations, exposure to high amounts of Pitocin (oxytocin) and/or opioids during birth, food allergies, and vitamin and mineral deficiencies.
Most ASD patients have elevated blood levels of serotonin, norepinephrine, and elevated dopamine metabolism resulting in elevated levels of homovanillic acid (HVA) (Launay et al, 1988; Lake et al, 1977; Hranilovic et al, 2007; Gillberg & Svennerholm, 1987).
Currently only one medication, risperidone, has been approved by the FDA for the symptomatic treatment of irritability in autistic children. Several medications have been used “off-label” to help lessen some of the symptoms associated with ASD, but with limited effectiveness. Some of these medications are antipsychotic medications, antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs), alpha adrenergic agonists, anticonvulsants, and stimulants such as Ritalin or Provigil. (http://autism.about.com/od/treatmentoptions/p/drugtreatments.htm)
Reserpine, which as is described below is utilized in a preferred embodiment of the present invention, has been used in the past in connection with ASD, but only in much higher doses than in the present invention. Lehman et al in 1957 studied the effect of Reserpine in Autistic children: The optimal dosage range was determined by starting at 0.2 mg orally three times a day and gradually increased to a maximum daily dose of 9 to 12 mg. The study identified the optimum dose of reserpine to be 3 to 7 mg per day with an average of 5 mg per day, and only while a child's dose was within this optimum dosage range were improvements observed (Lehman et al, 1957). A more recent article states that reserpine in doses of 0.25-1.8 mg/day may be effective in autism. (Macready, June 2001); although this article describes doses less than the optimal doses of 3-7 mg taught by Lehman et al, the 0.25-1.8 mg/day dosage range taught by Macready is still far higher than the dosage range of the present invention. Although showing some positive results, it is believed that the testing in Lehman et al and Macready has met with only limited success due to inaccurate assumptions concerning the neurological connections underlying the disorders, leading to use of excessively high dosages of reserpine. Moreover, the high dosages of reserpine tend to exacerbate the side effects associated with the compound.
Schizophrenia is a chronic disabling brain disorder that affects 1.1 percent of the U.S. population age 18 and older (National Institute of Mental Health, www.nimh.nih.gov/health/topics/schizophrenia/index.shtml).
The common signs and symptoms associated with schizophrenia are hallucinations, hearing voices, belief that thoughts are being broadcast to the world, paranoia that others are plotting harm, delusions, disordered thinking, movement disorders, flat affect, social withdrawal, agitation, aggressive behavior and cognitive deficits. These typical symptoms can be so debilitating that the sufferer of the disorder cannot maintain employment or relationships with others. Schizophrenic patients constitute a large percentage of the nation's homeless population.
Many of the symptoms of schizophrenia are similar to the symptoms of major depression and Bipolar Depressive Disorder as well as Autism Spectrum Disorder (ASD). Epidemiological data are consistent with an individual and familial overlap between Bipolar Depressive Disorder and Schizophrenia. It has been proposed in the literature that the two diseases are on the same continuum with varying levels of severity. (Lake & Hurwitz, 2007; Demily et al, 2009) Moreover, it has been shown that Major Depression, Bipolar Depressive Disorder, and Schizophrenia all have similar mitochondria complex I dysfunction that varies only in the anatomical sites where this deficiency exists (Ben-Shachar & Karry, 2008).
Accordingly, there exists a need for a method for treatment of neurologic dysfunctions relating to Major Depression, Autism Spectrum Disorder (ASD) and Schizophrenia, that approaches the root cause of the disorders in a more direct manner than treatments and therefore provides treatment with a greater degree of effectiveness. Still further, there exists a need for such a method that with reduced negative side effects as compared with prior treatments. Still further, there exists a need for such a method that is easy to implement and can be made available on a widespread basis to the many sufferers of such disorders.